opisthorchiasis: an overlooked danger
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Opisthorchiasis: An Overlooked DangerLudmila M. Ogorodova1, Olga S. Fedorova1*, Banchob Sripa2, Viatcheslav A. Mordvinov3,Aleksei V. Katokhin3, Jennifer Keiser4,5, Peter Odermatt5,6, Paul J. Brindley7, OlegA. Mayboroda8,9, Thirumalaisamy P. Velavan10, Maxim B. Freidin11,12, Alexey E. Sazonov1,Irina V. Saltykova1, Mariya Y Pakharukova3,13, Yulia V. Kovshirina1, Kostas Kaloulis14,Olga Y. Krylova15, Maria Yazdanbakhsh16, the TOPIC Consortium
1 Siberian State Medical University, Tomsk, Russian Federation, 2 Tropical Disease Research Laboratory,Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand, 3 Laboratory ofMolecular Mechanisms of Pathological Processes, Institute of Cytology and Genetics, Siberian Branch of theRussian Academy of Sciences, Novosibirsk, Russian Federation, 4 Department of Medical Parasitology andInfection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland, 5 University of Basel, Basel,Switzerland, 6 Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute,Basel, Switzerland, 7 Department of Microbiology, Immunology and Tropical Medicine, and Research Centerfor Neglected Diseases of Poverty, School of Medicine & Health Sciences, GeorgeWashington University,Washington, D.C., United States of America, 8 Center for Proteomics and Metabolomics, Leiden UniversityMedical Center, Leiden, the Netherlands, 9 Department of Chemistry, Tomsk State University, Tomsk,Russian Federation, 10 Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany,11 Academic Division of Thoracic Surgery, Royal Brompton Hospital, London, United Kingdom,12 Population Genetics Laboratory, Research Institute for Medical Genetics, Siberian Branch of RussianAcademy of Medical Sciences, Tomsk, Russian Federation, 13 Department of Natural Sciences, NovosibirskState University, Novosibirsk, Russian Federation, 14 ReMedys Foundation, Geneva, Switzerland,15 External R&D Innovation, Pfizer Russia, Moscow, Russian Federation, 16 Department of Parasitologyand Leiden Parasite Immunology Group, Leiden University Medical Center, Leiden, the Netherlands
BackgroundA group of helminth infections, caused by liver flukes of the trematode family Opisthorchiidae,were recently the focus of discussions at a meeting where scientists from Russia, SoutheastAsia, Europe, and the United States came together in Tomsk city in Western Siberia (Russia) toform a Tomsk OPIsthorchiasis Consortium (TOPIC). This initiative starts a platform to raiseawareness, to strengthen integrated control, and to conduct research on a neglected infectiousdisease that afflicts populations not only in the tropical regions of East Asia but also in temper-ate and semi-arctic areas of Europe and Asia [1].
The Opisthorchiidae of importance to humans are Opisthorchis felineus, Opisthorchis viver-rini, and Clonorchis sinensis, each of which has a discrete, though occasionally overlapping,geographical distribution: O. felineus is endemic in Europe and Russia; C. sinensis in China, theRepublic of Korea, and northern Vietnam; and O. viverrini in Southeast Asia. Together they af-fect more than 45 million people worldwide [2]. Human infection with O. felineus results fromeating raw or undercooked freshwater fish carrying the metacercariae of the parasite. The in-gested larvae develop further and migrate to the bile ducts by chemotaxis, where adult wormsfeed on biliary epithelia and contents in the bile. Adult worms shed eggs that enter the gastroin-testinal tract and are released with the faeces to the external environment. Freshwater snails ofthe family Bithyniidae ingest the eggs and, following the release of the miracidia from the eggs,several stages of development take place within the snail until cercariae have developed. Shedcercariae can penetrate freshwater fish, where they encyst in the skin or flesh [3].
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OPEN ACCESS
Citation: Ogorodova LM, Fedorova OS, Sripa B,Mordvinov VA, Katokhin AV, Keiser J, et al. (2015)Opisthorchiasis: An Overlooked Danger. PLoS NeglTrop Dis 9(4): e0003563. doi:10.1371/journal.pntd.0003563
Editor: Malcolm K. Jones, University of Queensland,AUSTRALIA
Published: April 2, 2015
Copyright: © 2015 Ogorodova et al. This is an openaccess article distributed under the terms of theCreative Commons Attribution License, which permitsunrestricted use, distribution, and reproduction in anymedium, provided the original author and source arecredited.
Funding: The International Scientific Conference“Opisthorchiasis. Overlooked danger” (14th-15th ofApril, 2014; Tomsk; Russian Federation) wassupported by the Pfizer LLC, Russian Foundation forBasic Research (grant N 14-04-060094; grant N NК14-04-31752/14) and Tomsk Oblast Government. Thefunders had no role in study design, data collectionand analysis, decision to publish, or preparation ofthe manuscript.
Competing Interests: I have read the journal's policyand the authors of this manuscript have the followingcompeting interests: OYK is employed by acommercial company, Pfizer LLC. This does not alterour adherence to all PLOS NTDs policies on sharingdata and materials.
Within the genus Opisthorchis, O. felineus is the species with the highest zoonotic potential,which has important implications not only for veterinary medicine but also for maintenance oftransmission to humans even under high hygienic standards in which the risk of freshwatercontamination by human faeces is low [4]. The morbidities associated with opisthorchiasis arelargely hepatobiliary, specifically stemming from bile duct fibrosis and cholangitis, and are ex-pressed in a variety of manifestations, such as obstructive jaundice, hepatomegaly, abdominalpain, and nausea [5]. Importantly, there are studies in animal models supported by other epide-miologic data that indicate that O. viverrini and C. sinensis infections can lead to cholangiocar-cinoma, a generally incurable and, hence, fatal bile duct cancer [6,7], which has resulted in theclassification of these parasites to the Group 1 carcinogens by the International Agency for Re-search on Cancer [1,8,9]. Despite the unarguable public health importance of these infections,both in terms of numbers of humans infected worldwide and clinical impact, it has been givenrelatively little recognition by health authorities, grant-giving agencies, and the pharmaceuticalindustry. There has been an incremental increase in awareness following seminal work in Thai-land, Korea, and, later, in China, Laos, and Cambodia, where a number of studies have clarifiedthe situation regarding epidemiology, pathogenesis, and control. Notably, genome sequence in-formation on these liver flukes is increasingly available, for example, at www.trematode.net[10]. However, important gaps remain and, in particular, there is a paucity of information re-garding O. felineus.
Therefore, an initiative was taken to organize a meeting in Tomsk, a city located in the re-gion of Western Siberia that is highly endemic for O. felineus [4,11], and bring together a multi-disciplinary cadre of investigators working on the Opisthorchiidae and infections caused bythese fish-borne liver flukes. This event was welcomed by Pfizer, a multinational pharmaceuti-cal company that supported the meeting, and that recognized the importance of infection withO. felineus as a neglected health threat in Russia. The meeting aimed to highlight the ongoingpublic health activities and research on diseases caused by Opisthorchiidae and, in particular,to identify the gaps in our knowledge of the epidemiology, clinical profile, treatment, and fun-damental mechanisms of host–parasite interaction.
Scientists presenting and discussing their research findings covered a spectrum of topicsthat included epidemiology and clinical aspects of these infections, as well as aspects of host–parasite interaction and the molecular biology of these parasites.
Epidemiology, Clinical Features, and TreatmentThe body of data available on the epidemiology of Opisthorchiidae comes largely from studiesconducted on infections with O. viverrini, and increasingly with C. sinensis, in which robustdata have been, and are being, collected in Southeast Asia to map the endemic regions and toquantify the extent of the morbidity associated with the infections [2]. Peter Odermatt fromthe Swiss Tropical and Public Health Institute discussed the importance of this infection inrural areas of Thailand, Laos, Cambodia, and Vietnam [12]. In particular, the infection is wide-spread in Laos, where more than half of the population is infected; in highly endemic villages,70% of the population is infected. Based on microscopy, 50% of the population in some villagesin Laos was found to be infected with O. viverrini, with an increasing prevalence of infectionwith age [13]. Close correlation has been found between consumption of fish and prevalence ofO. viverrini in communities in rural Laos where 23 different species of fish in the region can beinfected, and, in some villages, up to 60% of some of these fish species carry the metacercariae[14]. Examination of cats and dogs that are often coinhabitants of households revealed that30% of these domestic animals were infected with O. viverrini, and, thus, can contribute to
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intensifying transmission of these parasites to humans. Furthermore, the deeply culturallyrooted habit of raw fish dish consumption is a major public health challenge [15].
Data collected on the clinical symptoms have provided a comprehensive view on the mor-bidities associated with O. viverrini, reporting that increasing intensity of infection and multi-parasitic infection was associated with increasing reported symptoms of abdominal discomfortand disease in endemic communities [16–18]. The use of ultrasonography in the field has en-abled conduct of large-scale examination of inhabitants of affected villages to accurately delin-eate the abnormalities associated with the infection [19]. In the infected population examinedso far, normal hepatobiliary images generally were not observed, whereas mild and severe pa-thology with bile duct dilation was recorded in a high proportion of the adult population inrural areas [20].
The association between O. viverrini and cholangiocarcinoma, or bile duct cancer, was dis-cussed by Banchob Sripa from Khon Kaen University, Thailand. Not only is the highest inci-dence of this bile duct cancer in the world seen in Northeast Thailand, where O. viverrini ishighly endemic, but there is also compelling evidence from models using experimental infec-tion of laboratory rodents demonstrating the close association between the liver fluke and can-cer [21]. Whereas there is also considerable evidence for the association of C. sinensis and bileduct cancer, so far it is unknown whether O. felineus shares this feature, a clear area in whichfurther research is warranted [1].
There are ongoing efforts to understand the risk factors for the development of severe mor-bidity including the bile duct cancer: coinfection with other parasitic or viral (hepatic) infec-tions or smoking may be important. Large multi-centre and multi-country studies are neededto accurately map parasitic infection and risk factors for morbidity, including biomarkers forcholangiocarcinoma. Remote sensing and spatial Bayesian statistics that allow mapping of in-fection based on geophysical characteristics of the endemic areas are important tools to bringsociodemographic and environmental factors into the picture and, hence, prepare large-scalecorrelation maps of various risk factors and morbidity, including bile duct cancer [13]. At thebiological level, metabolic phenotyping of subjects at risk of developing cholangiocarcinomausing body fluids was explained by Oleg Mayboroda from Leiden University Medical Center,the Netherlands. The use of enabling analytical technologies such as mass spectrometry (MS)and Nuclear Magnetic Resonance spectroscopy (NMR), now more accessible than before, canbe helpful for early detection as well as understanding the mechanisms that lead to the develop-ment of cancer in infected subjects. Another area for application of the technologies is identifi-cation of metabolic profiles that are specific for Opisthorchiidae, as already done for otherparasitic infections [22–24], which might then allow the development of simple field applicablerapid tests.
Currently, the treatment of Opisthorchiidae is based on giving praziquantel at 40 mg/kgbody weight. Data presented by Peter Odermatt indicated that it might be necessary to increasethe dose of praziquantel to 75 mg/kg, but at the risk of increasing adverse events, which is animportant factor for community compliance [25]. The search for new therapies that are moreeffective and have reduced adverse events has come up with potential new drugs, such as tri-bendimidine [26–28].
Host–Parasite InteractionA number of basic mechanisms of host–parasite interaction regarding pathology and persis-tence were discussed. Banchob Sripa presented data on the ability of a number of parasite-de-rived molecules to drive uncontrolled growth of host cells and, thus, explain the possibleassociation between O. viverrini and bile duct cancer. Molecules such as parasite-derived
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granulin, which leads to proliferation of biliary and other mammalian cells [29], or parasite-de-rived enzymes thioredoxin (TRX) and thioredoxin peroxidase (TPX), which prevent apoptosis,could be involved in stimulating uncontrolled growth of host cells [3]. Moreover, there are dataindicating that O. viverrini extracts are able to stimulate inflammatory cytokines, such as IL-6and IL-8 by human cholangiocytes, peripheral blood mononuclear cells, and that a higher levelof IL-6 is seen in infected patients with bile duct cancer compared to those without [30–32].Together, these data raise the question of whether the other Opisthorchiidae have strong proin-flammatory properties that would explain the increased risk of cancer upon infection withthese trematodes and open possibilities for prevention.
Linked to the inflammatory response induced by O. viverrini, Paul Brindley from GeorgeWashington University, Washington, D.C., US, discussed the alteration in the gut and bilemicrobiome of infected hosts. He presented findings that reveal that infection with O. viverrinimodified the gut microbiome in hamsters. This investigation detected the unexpected presenceof communities of very select species of bacteria in the bile of infected hamsters. Intriguingly, anumber of species of environmental bacteria, and therefore not expected in the gut microflora,seemed to find their way into the bile along with O. viverrini. Might these microbes play an im-portant role in driving chronic inflammation in the bile tract? These bacterial species were dis-similar to endosymbiotic Neorickettsia species known to be associated with trematodes at large[33]. Nonetheless, given that laboratory contamination can impact sequence-based micro-biome analyses, especially in analysis of biofluids discrete from gut contents and faeces andwhere microbiota might be sparse [34], these findings will need to be confirmed in other set-tings. If, indeed, O. viverrinimetacercariae and/or developing adult flukes vector environmen-tal or exotic microbes into the biliary tree, persistent inflammatory responses to this fluke-associated microbiota could be a key factor in the development of cancer [3,19,21,35]. This re-port has paved the way for human studies to test whether similar mechanisms could be at play.
The basic immunological profile in humans infected with these parasites was the subject ofthe presentations by Olga Fedorova from Siberian State Medical University and Maria Yazdan-bakhsh from Leiden University Medical Center, the Netherlands. In comparison with otherparasitic helminths, relatively little has been done on the immunological profiling of humansinfected with Opisthorchiidae, especially beyond O. viverrini infections [30]. The immunoepi-demiological studies in the region of Tomsk comparing subjects infected with and without O.felineus has indicated that there is TH2 skewing as evident from elevated IgE in infected sub-jects compared to uninfected, but that the levels are much lower than what is found in studiesof helminth infected subjects in Ghana where schistosomiasis is highly prevalent or in Indone-sia in communities with geohelminth infections. This could result from the fact that intensityof infection is lower in O. felineus infected subjects and that there are much less coinfectionswith other helminths in semi-arctic regions of Western Siberia. However, it is also possible thatthe antigenic composition of the O. felineus is less capable of inducing TH2 responses. Someevidence for this comes from in vitro studies in which human dendritic cells cultured with O.felineus antigens lead to less TH2 skewing compared to when dendritic cells were cultured withSchistosoma mansoni antigens [36].
The skewing of immune responses towards TH1, TH2, and regulatory T cells can be impor-tant for understanding immunopathological processes as well as the development of cancer as-sociated with an infection. A number of studies of humans chronically infected with, forexample, schistosomes or geohelminths have shown the induction of regulatory T [37,38] andB cells [39] by these parasites. These immune regulatory cells can be involved in the suppres-sion of responses to unrelated antigens [40,41]. A study conducted in the Tomsk region hasshown an inverse association between O. felineus and responses to allergens [11], supportingthe notion that it would be worthwhile to investigate whether Opisthorchiidae are able to
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induce regulatory cells. This is of particular importance also because of the possible link to thedevelopment of cancer. Prognosis of cancer is poor if regulatory T cells are found in tumoursand a number of studies in experimental models have indicated that regulatory T cells are asso-ciated with faster tumour growth [42,43]. Whether O. viverrini and C. sinensis bear moleculesthat are able to induce regulatory T or B cells should be investigated. Recently, the excretory/se-cretory (E/S) antigens of a nematode, Heligmosomoides polygyrus, have been shown to drivestrong regulatory T cell responses. Neutralisation of these E/S antigens resulted in completeelimination of the worms [44]. This exciting approach could also be considered for driving im-munity to Opisthorchiidae as well as fighting against the associated bile duct cancer.
A presentation by Thirumalaisamy Velavan, representing the Institute of Tropical Medi-cine, University of Tuebingen, Germany, indicated the importance of studies regarding the in-nate immune components of the complement system and its interaction with Opisthorchiidae.O. felineus has an outer syncytial cytoplasmic layer as teguments, such as in other trematodes.Earlier studies have demonstrated that these trematode teguments are made up of D-mannose/D-glucose, N-acetyl-D-glucosamine/sialic acid, D-galactose, and N-acetyl-D-galactosamineresidues on the glycocalyx of the adult tegument and are expressed at all developmental stages.These glycoconjugates serve as pathogen-associated molecular patterns (PAMPs) for immunerecognition and subsequent complement-mediated killing [45–47]. Two innate immune recog-nition elements of the complement system, the mannose-binding lectin and ficolins, were earli-er shown to influence the infection outcome in S. haematobium that causes urinary bladdercancer [48,49]. Additionally, the functional variants of theseMBL2 and FCN2 genes were es-tablished to modulate the circulating serum levels and the binding capacity to the parasite sur-face, thus leading to impaired recognition [50]. Hence, investigation of the lectin pathwayproteins during Opisthorchis infection might help in better understanding the interactions be-tween the host and the parasite during an establishment of active infection.
Indeed, the question of genetic regulation of susceptibility to Opisthorchiidae and geneticcontrol of the development of associated pathology requires attention. Maxim Freidin from theResearch Institute for Medical Genetics, Russia, and Royal Brompton Hospital, United King-dom, showed the results of a pilot gene–environment interaction study in the Tomsk popula-tion that identified O. felineus infection as an important modifier of associations between TH1/TH2-regulating genes and allergic disease. In particular, it was shown that O. felineus infectiondiminishes the risk of atopic bronchial asthma associated with the polymorphisms of theSOCS5 and IFNG genes [4]. The allele specific gene expression was found to be modified by thepresence of O. felineus antigens, thus providing a functional clue for the mechanisms of theidentified gene–environment interaction. These studies form a paradigm for assessing whethertissue pathology/cancer development is controlled by inflammation as a result of gene–environment interaction.
DiagnosisAttempts to use molecular approaches to detect O. felineus in hospital-based studies in Europewhere infections are found sporadically have been described [51]. A presentation by Vasily Pet-renko fromMedical Biological Union and Institute of Cytology and Genetics, Novosibirsk,Russia, showed promising results on the detection of four Opisthorchiidae flukes, O. felineus inparticular, by Taqman-based real-time PCR with a high degree of sensitivity and specificitywhen working with faeces from hamsters infected with local strains. These results call forlarge-scale validation studies similar to ongoing activities regarding the molecular diagnosis ofO. viverrini and C. sinensis and reliable discrimination of O. felineus infection [2]. Field applica-bility of these tests was discussed in terms of providing point of care diagnostic assays.
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Thirumalaisamy Velavan presented a new molecular diagnostic approach for rapid detectionof parasites using the Loop-mediated isothermal amplification (LAMP) method [52]. Thesemethodologies were established for O. viverrini targeting the internal transcribed spacer 1(ITS1) in ribosomal DNA for specific amplification [53]. LAMPmethodologies are simple, sen-sitive, specific, and faster than PCR, requiring minimal processing and instrumentation, withresults available by reading with the naked eye. The development of such a LAMPmethodologyfor O. felineus is being established.
Parasite Biology and Drug TargetsThe research group of the Institute of Cytology and Genetics in Novosibirsk, under the leader-ship of Aleksei Katokhin, has conducted phylogeographic genetics studies of Opisthorchiidaeflukes in order to compare their genetic diversities and species histories [54]. These studies areaimed at explaining pronounced differences in capacities of the three flukes to parasitize in var-ious mammals and shedding light on the degree of zoonosis of the different species [2]. Thesestudies might help integrated control programs and further our fundamental understanding ofbiological processes.
Mariya Pakharukova and Viatcheslav Mordvinov, also at the Institute of Cytology and Ge-netics, Novosibirsk, presented data on the structure and functional organization of xenobioticbiotransformation system in O. felineus [55]. The system participates, probably, in O. felineusmetabolism and in the transport of endogenous and exogenous substrates. Importantly, cyto-chrome P450 is expressed differentially through the life cycle of O. felineus and is present in O.felineus in higher amounts than in O. viverrini. The question is whether this could have any re-lationship to synthesis of proinflammatory and potentially carcinogenic compounds, e.g., oxy-sterol-like, catechol estrogen quinone-like, etc., released by the flukes [56,57]. Novel data werealso presented on studies on praziquantel effects in the O. felineus hamster model and in vitroon juvenile and adult worms, particularly, about parasite motility, viability, and tegument dam-age after praziquantel treatment.
Concluding Remarks: Call for Expansion of the ConsortiumThe data presented and discussed led us to the conclusion that there are many groups withoverlapping interests and relevant expertise that are willing to work together towards the com-mon aim of controlling liver fluke infections and associated pathologies worldwide. Most im-portantly, it was stressed that this is a starting point for inviting other groups actively workingin the field of liver fluke research to join the Tomsk Opisthorchiasis Consortium by contactingLudmila Ogorodova from Siberian State Medical University, Tomsk, Russia ([email protected]). In particular, since there was only limited discussion of the current stateof research in the area of clonorchiasis, specialists from this field would also be especiallywelcome.
The Tropical Disease Research Laboratory at Khon Kaen University has a successful controlprogram, the so called “Lawa model,” based on using the EcoHealth approach at the lake Lawaregion of Northeast Thailand [58]. It was agreed that this control model will be taken as a tem-plate and modified according to local health care systems and cultural sensitivities in other en-demic areas, but not differing in essence of involving trans-disciplinary and stakeholderparticipation at every level.
One of the first issues to be addressed is to understand the knowledge gap on the prevalenceof O. felineus infection in Russia and the extent of the related morbidity; in particular, whetheran O. felineus infection is associated with an increased risk of bile duct cancer. In parallel, activ-ities that facilitate faster development of validated diagnostic tests to accurately detect O.
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felineus infection will be stimulated and treatment efficacies of currently used drugs verified,while groups will work together in order to strengthen the scientific and technological skillsneeded to understand the host–parasite interaction in terms of immune-pathogenesis and reg-ulation. Finally, the overarching, fundamental molecular biological efforts to identify new drugtargets or new preventive and therapeutic measures will be stimulated by combining expertiseand sharing biological material available within the Consortium.
The Consortium shall operate through, and expand towards, several parallel research collab-orative activities/work packages, depicted in the high level roadmap (Fig. 1), such as: burden/severity and control at the community; clinical studies; biology, and ecology of parasites; host–parasite interactions; knowledge/technology transfer.
These activities are detailed in an under-development project plan. The success of the Con-sortium shall be measured upon the delivery of research results, and, in long-term, through theapplicability of these results to the society. Thus, care shall be given to the technology transfer,through all available and feasible mechanisms, bridging the gap between basic research andindustrialization. To secure the planning, the establishment, the coordination, the advance-ment, the milestones reaching, and, finally, the knowledge/technology transfer of the results,the on-board availability of expertise in program management and industrialization will be pri-oritized. This can be through entities with industrial expertise such as Pfizer and the ReMedysFoundation, who are both already among the founding members of the Consortium. (Pfizerstrives to positively impact the health of people around the world. Pfizer’s corporate social in-vestment strategy focuses on leveraging the full range of the company's resources—people,skills, expertise, and funding—to broaden access to medicines and strengthen health care deliv-ery for underserved people around the world [http://www.pfizer.com/responsibility/global_health/global_health]. ReMedys is a not-for-profit entity, founded by biopharmaceutical indus-try experts, intending to implement a novel, highly collaborative approach bridging the gap of
Fig 1. Consortium high level timelines/activities. 1. Siberian State Medical University, Tomsk, Russian Federation, 2. Center for Proteomics andMetabolomics, Leiden University Medical Center, Leiden, the Netherlands, 3. Department of Parasitology and Leiden Parasite Immunology Group, LeidenUniversity Medical Center, Leiden, the Netherlands, 4. GeorgeWashington University Medical Center, United States, 5. Institute of Cytology and Genetics,Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russian Federation, 6. Institute of Tropical Medicine, University of Tübingen, Germany,7. Khon Kaen University, Khon Kaen, Thailand, 8. Pfizer LLC, Moscow, Russian Federation, 9. ReMedys Foundation, Geneva, Switzerland, 10. RoyalBrompton Hospital, United Kingdom; Research Institute for Medical Genetics, Tomsk, Russian Federation, 11. Swiss Tropical and Public Health Institute,Basel, Switzerland.
doi:10.1371/journal.pntd.0003563.g001
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translational Research and Development [R&D]. ReMedys acts as the translational R&D armand hub for top research institutions, patient groups, and clinicians. Via building and coordi-nating customized patient centric alliances, ReMedys brings together all resources needed toadvance, and make available to patients with high unmet need, promising therapeutic projects[http://remedys.net].)
The founding members of the Consortium have signed a Memorandum of Understand-ing, which shall be available for the signature of research groups interested to become newmembers.
The overall program shall be regulated by a Consortium agreement that is under establish-ment, to which new members shall be invited to join and participate. The funding for the Con-sortium shall be secured through national and international grants-associated activities by themembers. As described, the Consortium aims to engage into a strategic collaborative study ona serious, but highly neglected, infectious disease, which is responsible for a heavy socioeco-nomic burden including cancer. The study shall concentrate, as well, into sensitive populationssuch as children, and, hence, expects to deliver findings with a high socioeconomic impact.Thus, the Consortium, with appropriate tools, can develop enhanced public awareness throughthe patient, the doctor, the researcher, the grant sponsor, and the government. Such an aware-ness shall support its funding through, as well, public, philanthropic, international NGOs; cor-porate responsibility partnerships; and so forth. Other funding mechanisms, such as crowdfunding, in which all the Consortium members can participate, shall be explored.
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